Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. We have demonstrated that ex-vivo stimulation with M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation by engaging non-inflammasome dependent innate pathways. We have shown in a Phase 1a clinical study that M2SR is generally safe and well-tolerated with the ability to elicit immune responses in seronegative, seropositive and seroprotected subjects. Subsequently, we showed that M2SR recipients provided protection against a highly drifted influenza virus. In this proposal, we will explore the ability of M2SR to stimulate antiviral immune responses in older subjects in the following aims: Aim 1. Conduct Phase 1b study testing safety and immunogenicity of M2SR in older subjects. Aim 2. Evaluate immune responses from older human subjects vaccinated with M2SR These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the immune responses that contribute to protective immunity. The outcome of the experiments is expected to have high impact with respect to the fundamental understanding of the ability of M2SR to elicit immune responses in the susceptible elderly population, and in demonstrating safety of an effective vaccine dosing regimen.